Pulmonary fibrosis is a progressive interstitial lung disease with a mean survival of 3-5 yrs. The underlying cause or genetic factors involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF) are unknown. Thus, little practical improvement has been made in treatment. While genetic changes are reported in two genes that regulate telomerase activity, these occur in only a small subset of individuals and clearly do not represent the majority of the patients with this disease. MicroRNAs (miRNA, miR) are regulatory RNAs that regulate gene expression by targeting mRNAs for degradation or preventing protein translation. It has been estimated that a single miRNA can regulate the expression of 20-30 proteins. The miR-17~92 miRNA cluster targets genes, such as metalloproteinases, collagen, and transforming growth factor that are highly expressed in IPF. Our preliminary data indicate that there are decreases in expression of the miR-17~92 miRNA cluster in the lungs from patients with IPF. We hypothesize that decrease expression of miRNAs contained within this cluster are critical for the pathogenesis of IPF. In this proposal, we will investigate the specific role of this miRNA cluster. We will also explore which members of this cluster are critical in the development and progression of IPF. Lastly, we determine if intervention in murine models of pulmonary fibrosis to replete the cluster can be effective treatment of this disease. For these goals we plan to investigate the following specific aims: Specific Aim 1: Determine the mechanisms and cell types involved in miR-17~92 suppression in IPF. Specific Aim 2: To define the impact of manipulating miR-17~92 cluster on cellular phenotype and gene expression in cells from patients with IPF. Specific Aim 3: To define the effect of manipulating miR-17~92 expression in a murine model of pulmonary fibrosis. PUBLIC HEALTH RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease with unknown etiology and a mean survival of 3-5 years survival. Despite ongoing studies to define the etiology of the disease, little practical improvement has been made in treatment and expected or observed outcomes. Complexity of IPF suggests that there are likely numerous interactions between a person's genes and environment. We speculate that searching for gene networks altered in patients with IPF would be a better approach to understand the disease. Since microRNAs can regulate multiple genes, we will focus on gene regulation through microRNAs in this proposal. We will use the integrative field of systems biology to classify and define molecular networks activated in these patients using miRNA and mRNA profiling of lung tissue. These data will be used to construct and predict gene networks that are activated in these patients to determine if the alterations can be used to classify and predict disease progression and severity as well as identify targets for therapeutic purposes.